Ruthenium-diamine complex and method for producing optically active compound

ABSTRACT

Provided is a ruthenium complex that is represented by general formula (1*) and is useful as an asymmetric reduction catalyst. 
     (In the formula, * is an asymmetric carbon atom; R 1  is an arenesulfonyl group, and the like; R 2  and R 3  are a phenyl group, and the like; R 10  through R 14  are selected from a hydrogen atom, C 1-10  alkyl group, and the like, but R 10  through R 14  are not simultaneously hydrogen atoms; X is a halogen atom and the like; j and k are each either 0 or 1; and j+k is 0 or 2.)

TECHNICAL FIELD

The present invention relates to a novel ruthenium-diamine complex, anda method for selectively producing optically active alcohols andoptically active amines, which are important as precursors forsynthesizing pharmaceuticals and functional materials, the method usingthe ruthenium-diamine complex as a catalyst.

BACKGROUND ART

Many asymmetric reactions including asymmetric reduction have beendeveloped, and many asymmetric reactions have been reported in whichasymmetric metal complexes having optically active phosphine ligands areused. On the other hand, many reports have shown that complexes in whichoptically active nitrogen compounds are coordinated to transitionmetals, such as ruthenium, rhodium, and iridium, for example, haveexcellent performances as catalysts for asymmetric synthesis reactions.Moreover, to enhance the performances of these catalysts, variousoptically active nitrogen compounds have been developed (Non PatentLiteratures 1, 2, 3, 4, etc.). In particular, M. Wills et al. havereported that complexes in which a diamine moiety and an aromatic ring(arene) moiety coordinated to the ruthenium complex are linked by acarbon chain exhibit higher activities than conventional catalysts (NonPatent Literatures 5, 6, 7, 8, 9, 10, etc.).

CITATION LIST Non Patent Literatures

-   Non Patent Literature 1: Chem Rev. (1992), p. 1051-   Non Patent Literature 2: J. Am. Chem. Soc. 117 (1995), p. 7562-   Non Patent Literature 3: J. Am. Chem. Soc. 118 (1996), p. 2521-   Non Patent Literature 4: J. Am. Chem. Soc. 118 (1996), p. 4916-   Non Patent Literature 5: J. Am. Chem. Soc. 127 (2005), p. 7318-   Non Patent Literature 6: J. Org. Chem. 71 (2006), p. 7035-   Non Patent Literature 7: Org. Biomol. Chem. 5 (2007), p. 1093-   Non Patent Literature 8: Org. Lett. 9 (2007), p. 4659-   Non Patent Literature 9: J. Organometallic. Chem. 693 (2008), p.    3527-   Non Patent Literature 10: Dalton. Trans. 39 (2010), p. 1395

SUMMARY OF INVENTION

However, conventional asymmetric synthesis methods using any of thesecomplexes result in insufficient catalytic activity or insufficientenantiomeric excess in some cases depending on the target reaction orthe reaction substrate of the reaction. Hence, further development of acomplex has been desired.

The present inventors have focused on the chain moiety which links thearene moiety coordinated to ruthenium and the diamine moiety, and havefound that a complex in which (i) at least one substituent is present onthe aromatic ring in the arene moiety, and (ii) the length of the carbonchain of the linking chain moiety is 4 has a high catalytic activity andachieves an excellent enantiomeric excess.

Specifically, the present invention includes the following contents.

[1] A ruthenium complex represented by the following general formula(1):

wherein R¹ represents an alkyl group having 1 to 10 carbon atoms; analkanesulfonyl group having 1 to 10 carbon atoms and optionallysubstituted with a halogen atom; an arenesulfonyl group optionallysubstituted with an alkyl group having 1 to 10 carbon atoms, ahalogenated alkyl group having 1 to 10 carbon atoms, or a halogen atom;an alkoxycarbonyl group having 2 to 11 carbon atoms in total; or abenzoyl group optionally substituted with an alkyl group having 1 to 10carbon atoms, R² and R³ each independently represent an alkyl grouphaving 1 to 10 carbon atoms; a phenyl group optionally substituted withan alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to10 carbon atoms, or a halogen atom; or a cycloalkyl group having 3 to 8carbon atoms, or R² and R³ may together form a ring, R¹⁰ to R¹⁴ eachindependently represent a hydrogen atom, an alkyl group having 1 to 10carbon atoms, an alkoxy group having 1 to 10 carbon atoms, or atrialkylsilyl group, provided that the case where all of R¹⁰ to R¹⁴simultaneously represent hydrogen atoms is excluded, X represents atrifluoromethanesulfonyloxy group, a p-toluenesulfonyloxy group, amethanesulfonyloxy group, a benzenesulfonyloxy group, a hydrogen atom,or a halogen atom, j and k each represent 0 or 1, and j+k is 0 or 2.[2] A ruthenium complex represented by the following general formula(1*):

wherein each * represents an asymmetric carbon atom, R¹ represents analkyl group having 1 to 10 carbon atoms; an alkanesulfonyl group having1 to 10 carbon atoms and optionally substituted with a halogen atom; anarenesulfonyl group optionally substituted with an alkyl group having 1to 10 carbon atoms, a halogenated alkyl group having 1 to 10 carbonatoms, or a halogen atom; an alkoxycarbonyl group having 2 to 11 carbonatoms in total; or a benzoyl group optionally substituted with an alkylgroup having 1 to 10 carbon atoms, R² and R³ each independentlyrepresent an alkyl group having 1 to 10 carbon atoms; a phenyl groupoptionally substituted with an alkyl group having 1 to 10 carbon atoms,an alkoxy group having 1 to 10 carbon atoms, or a halogen atom; or acycloalkyl group having 3 to 8 carbon atoms, or R² and R³ may togetherform a ring, R¹⁰ to R¹⁴ each independently represent a hydrogen atom, analkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10carbon atoms, or a trialkylsilyl group, provided that the case where allof R¹⁰ to R¹⁴ simultaneously represent hydrogen atoms is excluded, Xrepresents a trifluoromethanesulfonyloxy group, a p-toluenesulfonyloxygroup, a methanesulfonyloxy group, a benzenesulfonyloxy group, ahydrogen atom, or a halogen atom, j and k each represent 0 or 1, and j+kis 0 or 2.[3] A ruthenium complex represented by the following general formula(1′):

wherein each * represents an asymmetric carbon atom, R¹ represents analkyl group having 1 to 10 carbon atoms; an alkanesulfonyl group having1 to 10 carbon atoms and optionally substituted with a halogen atom; anarenesulfonyl group optionally substituted with an alkyl group having 1to 10 carbon atoms, a halogenated alkyl group having 1 to 10 carbonatoms, or a halogen atom; an alkoxycarbonyl group having 2 to 11 carbonatoms in total; or a benzoyl group optionally substituted with an alkylgroup having 1 to 10 carbon atoms, R² and R³ each independentlyrepresent an alkyl group having 1 to 10 carbon atoms; a phenyl groupoptionally substituted with an alkyl group having 1 to 10 carbon atoms,an alkoxy group having 1 to 10 carbon atoms, or a halogen atom; or acycloalkyl group having 3 to 8 carbon atoms, or R² and R³ may togetherform a ring, R¹⁰ to R¹⁴ each independently represent a hydrogen atom, analkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10carbon atoms, or a trialkylsilyl group, provided that the case where allof R¹⁰ to R¹⁴ simultaneously represent hydrogen atoms is excluded, andQ⁻ represents a counter anion.[4] A ruthenium complex represented by the following general formula(2), or a salt thereof:

wherein R¹ represents an alkyl group having 1 to 10 carbon atoms; analkanesulfonyl group having 1 to 10 carbon atoms and optionallysubstituted with a halogen atom; an arenesulfonyl group optionallysubstituted with an alkyl group having 1 to 10 carbon atoms, ahalogenated alkyl group having 1 to 10 carbon atoms, or a halogen atom;an alkoxycarbonyl group having 2 to 11 carbon atoms in total; or abenzoyl group optionally substituted with an alkyl group having 1 to 10carbon atoms, R² and R³ each independently represent an alkyl grouphaving 1 to 10 carbon atoms; a phenyl group optionally substituted withan alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to10 carbon atoms, or a halogen atom; or a cycloalkyl group having 3 to 8carbon atoms, or R² and R³ may together form a ring, R¹⁰ to R¹⁴ eachindependently represent a hydrogen atom, an alkyl group having 1 to 10carbon atoms, an alkoxy group having 1 to 10 carbon atoms, or atrialkylsilyl group, provided that the case where all of R¹⁰ to R¹⁴simultaneously represent hydrogen atoms is excluded, and X′ represents ahalogen atom.[5] A ruthenium complex represented by the following general formula(2*), or a salt thereof:

wherein each * represents an asymmetric carbon atom, R¹ represents analkyl group having 1 to 10 carbon atoms; an alkanesulfonyl group having1 to 10 carbon atoms and optionally substituted with a halogen atom; anarenesulfonyl group optionally substituted with an alkyl group having 1to 10 carbon atoms, a halogenated alkyl group having 1 to 10 carbonatoms, or a halogen atom; an alkoxycarbonyl group having 2 to 11 carbonatoms in total; or a benzoyl group optionally substituted with an alkylgroup having 1 to 10 carbon atoms, R² and R³ each independentlyrepresent an alkyl group having 1 to 10 carbon atoms; a phenyl groupoptionally substituted with an alkyl group having 1 to 10 carbon atoms,an alkoxy group having 1 to 10 carbon atoms, or a halogen atom; or acycloalkyl group having 3 to 8 carbon atoms, or R² and R³ may togetherform a ring, R¹⁰ to R¹⁴ each independently represent a hydrogen atom, analkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10carbon atoms, or a trialkylsilyl group, provided that the case where allof R¹⁰ to R¹⁴ simultaneously represent hydrogen atoms is excluded, andX′ represents a halogen atom.[6] A catalyst for asymmetric reduction, comprising the rutheniumcomplex according to [2], [3], or [5].[7] A method for producing an optically active alcohol, comprisingreducing a carbonyl group of a carbonyl compound in the presence of theruthenium complex according to [2], [3], or [5] and a hydrogen donor.[8] A method for producing an optically active amine, comprisingreducing an imino group of an imine compound in the presence of theruthenium complex according to [2], [3], or [5] and a hydrogen donor.[9] The production method according to [7] or [8], wherein

the hydrogen donor is selected from formic acid, alkali metal formates,and alcohols having a hydrogen atom on a carbon atom at an α-position ofa carbon atom substituted with a hydroxyl group.

[10] The production method according to [7] or [8], wherein

the hydrogen donor is hydrogen gas.

The present invention provides a novel ruthenium-diamine complex inwhich a diamine moiety and an arene moiety coordinated to the rutheniumcomplex is linked by a carbon chain. The ruthenium-diamine complex ofthe present invention has an extremely higher catalytic activity thanconventional hydrogen transfer-type complexes, and hence is useful asvarious hydrogenation catalysts. Moreover, the ruthenium complex of thepresent invention in which a substituent such as an alkyl group ispresent on the aromatic ring and the length of the carbon chain of thelinking chain moiety is 4 is excellent in stereoselectivity and achievesa high enantiomeric excess, and hence makes it possible to obtain atarget substance with a high optical purity and a high yield in ahydrogen transfer reaction or a hydrogenation reaction.

The use of the ruthenium-diamine complex of the present invention makesit possible to selectively produce optically active alcohols andoptically active amine, which are useful as a raw material for producingpharmaceuticals and functional materials and the like.

DESCRIPTION OF EMBODIMENTS

Hereinafter, the present invention will be described in further detail.

In the ruthenium complex represented by each of the general formulae(1), (1*), (1′), (2), and (2*), the alkyl group having 1 to 10 carbonatoms represented by R¹ is a linear or branched alkyl group having 1 to10 carbon atoms, and preferably 1 to 5 carbon atoms. Specific examplesof the alkyl group include a methyl group, an ethyl group, a n-propylgroup, an isopropyl group, a n-butyl group, an isobutyl group, a s-butylgroup, a t-butyl group, a n-pentyl group, a n-hexyl group, a n-heptylgroup, a n-octyl group, a n-nonyl group, a n-decyl group, and the like.

Examples of the alkanesulfonyl group having 1 to 10 carbon atomsrepresented by R¹ include a methanesulfonyl group, an ethanesulfonylgroup, a propanesulfonyl group, and the like. The alkanesulfonyl groupis optionally substituted with one or multiple halogen atoms. Examplesof the halogen atoms include chlorine atoms, bromine atoms, fluorineatoms, and the like. Examples of the alkanesulfonyl group having 1 to 10carbon atoms and substituted with a halogen atom include atrifluoromethanesulfonyl group, and the like.

Examples of the arenesulfonyl group represented by R¹ include abenzenesulfonyl group, and the like. The arenesulfonyl group isoptionally substituted with one or multiple alkyl groups having 1 to 10carbon atoms, halogenated alkyl groups having 1 to 10 carbon atoms, orhalogen atoms. The alkyl groups having 1 to 10 carbon atoms includethose listed as the alkyl group having 1 to 10 carbon atoms representedby R¹, and the like. The halogenated alkyl groups having 1 to 10 carbonatoms include halides of those listed as the alkyl group having 1 to 10carbon atoms represented by R¹ (examples of the halogen atoms includechlorine atoms, bromine atoms, fluorine atoms, and the like), and thelike.

Examples of the halogen atoms include chlorine atoms, bromine atoms,fluorine atoms, and the like. Examples of the arenesulfonyl groupsubstituted with an alkyl group having 1 to 10 carbon atoms, ahalogenated alkyl group having 1 to 10 carbon atoms, or a halogen atominclude a p-toluenesulfonyl group, a 2,4,6-trimethylbenzenesulfonylgroup, a 4-trifluoromethylbenzenesulfonyl group, apentafluorobenzenesulfonyl group, and the like.

The alkoxycarbonyl group having 2 to 11 carbon atoms in totalrepresented by R¹ may be a linear or branched alkoxycarbonyl grouppreferably having 2 to 5 carbon atoms in total, and specifically is amethoxycarbonyl group, an ethoxycarbonyl group, a t-butoxycarbonylgroup, or the like.

The benzoyl group represented by R¹ is optionally substituted with oneor multiple alkyl groups having 1 to 10 carbon atoms. The alkyl groupshaving 1 to 10 carbon atoms include those listed as the alkyl grouphaving 1 to 10 carbon atoms represented by R¹, and the like. The benzoylgroup optionally substituted with an alkyl group having 1 to 10 carbonatoms is a benzoyl group, a p-toluoyl group, an o-toluoyl group, or thelike.

The alkyl group having 1 to 10 carbon atoms represented by each of R²and R³ includes those listed as the alkyl group having 1 to 10 carbonatoms represented by R¹, and the like.

The phenyl group represented by each of R² and R³ is optionallysubstituted with one or multiple alkyl groups having 1 to 10 carbonatoms, alkoxy groups having 1 to 10 carbon atoms, or halogen atoms. Thealkyl groups having 1 to 10 carbon atoms include those listed as thealkyl group having 1 to 10 carbon atoms represented by R¹, and the like.The alkoxy groups having 1 to 10 carbon atoms are linear or branchedalkoxy groups having 1 to 10 carbon atoms, and preferably 1 to 5 carbonatoms. Specific examples of the alkoxy groups include methoxy groups,ethoxy groups, n-propoxy groups, isopropoxy groups, n-butoxy groups,isobutoxy groups, s-butoxy groups, t-butoxy groups, n-pentyloxy groups,n-hexyloxy groups, n-heptyloxy groups, n-octyloxy groups, n-nonyloxygroups, n-decyloxy groups, and the like. Examples of the halogen atomsinclude chlorine atoms, bromine atoms, fluorine atoms, and the like.Examples of the phenyl group substituted with an alkyl group having 1 to10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, or ahalogen atom include a 2,4,6-trimethylphenyl group, a 4-methoxyphenylgroup, a 2,4,6-trimethoxyphenyl group, a 4-fluorophenyl group, a2-chlorophenyl group, a 4-chlorophenyl group, a 2,4-dichlorophenylgroup, and the like.

The cycloalkyl group having 3 to 8 carbon atoms represented by each ofR² and R³ is a monocyclic, polycyclic, or bridged cycloalkyl grouphaving 3 to 8 carbon atoms, and preferably 5 to 8 carbon atoms. Specificexamples of the cycloalkyl group having 3 to 8 carbon atoms include acyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexylgroup, a cycloheptyl group, a cyclooctyl group, and the like. Thesecycloalkyl groups are optionally substituted with alkyl groups such asmethyl groups, isopropyl groups, and t-butyl groups, or the like.

Regarding the ring formed by R² and R³ together, R² and R³ together forma linear or branched alkylene group having 2 to 10 carbon atoms, andpreferably 3 to 10 carbon atoms, and thus form a preferably 4- to8-membered, more preferably 5- to 8-membered cycloalkane ring togetherwith the adjacent carbon atoms. Preferred examples of the cycloalkanering include a cyclopentane ring, a cyclohexane ring, and a cycloheptanering. These rings may have, as substituents, alkyl groups such as methylgroups, isopropyl groups, and t-butyl group, or the like.

The alkyl group having 1 to 10 carbon atoms represented by each of R¹⁰to R¹⁴ is a linear or branched alkyl group having 1 to 10 carbon atoms,and preferably 1 to 5 carbon atoms. Specific examples of the alkyl groupinclude a methyl group, an ethyl group, a n-propyl group, an isopropylgroup, a n-butyl group, an isobutyl group, a s-butyl group, a t-butylgroup, a n-pentyl group, a n-hexyl group, a n-heptyl group, a n-octylgroup, a n-nonyl group, a n-decyl group, and the like.

The alkoxy group having 1 to 10 carbon atoms represented by each of R¹⁰to R¹⁴ is a linear or branched alkoxy group having 1 to 10 carbon atoms,and preferably 1 to 5 carbon atoms. Specific examples of the alkoxygroup include a methoxy group, an ethoxy group, a n-propoxy group, anisopropoxy group, a n-butoxy group, an isobutoxy group, a s-butoxygroup, a t-butoxy group, a n-pentyloxy group, a n-hexyloxy group, an-heptyloxy group, a n-octyloxy group, a n-nonyloxy group, a n-decyloxygroup, and the like.

The alkyl groups of the trialkylsilyl group represented by each of R¹⁰to R¹⁴ are alkyl groups having 1 to 10 carbon atoms, and arespecifically methyl groups, ethyl groups, n-propyl groups, isopropylgroups, n-butyl groups, isobutyl groups, s-butyl groups, t-butyl groups,n-pentyl groups, n-hexyl groups, n-heptyl groups, n-octyl groups,n-nonyl groups, n-decyl groups, or the like. Specific examples of thetrialkylsilyl group include a trimethylsilyl group, a triethylsilylgroup, a t-butyldimethylsilyl group, a triisopropylsilyl group, and thelike.

Note that the case where all of R¹⁰ to R¹⁴ simultaneously representhydrogen atoms is excluded.

In the ruthenium complex represented by the general formula (1) or (1*),j and k are each an integer of 0 or 1, provided that the case where j+kis 1 is excluded. In other words, when k is 1, j is also 1, whereas whenk is 0, j is also 0.

When j is 1 in the ruthenium complex represented by the general formula(1) or (1*), X represents a trifluoromethanesulfonyloxy group, ap-toluenesulfonyloxy group, a methanesulfonyloxy group, abenzenesulfonyloxy group, a hydrogen atom, or a halogen atom, andpreferably is a halogen atom. The halogen atom is preferably a chlorineatom.

In the ruthenium complex represented by the general formula (2) or (2*),the halogen atom represented by X′ is preferably a chlorine atom.

Q⁻ in the general formula (1′) represents a counter anion. The counteranion is specifically an ion such as BF₄ ⁻, SbF₆ ⁻, CF₃COO⁻, CH₃COO⁻,PF₆ ⁻, NO₃ ⁻, ClO₄ ⁻, SCN⁻, OCN⁻, ReO₄ ⁻, MoO₄ ⁻, BPh₄ ⁻, B(C₆F₅)₄ ⁻, orB(3,5-(CF₃)₂C₆F₃)₄ ⁻.

The ruthenium complex represented by each of the general formulae (1),(1*), (2), and (2*) of the present invention can be produced, forexample, by a method according to Scheme 1 below. Note that although acase of the general formula (1*) or (2*) which represents an opticallyactive substance is described in Scheme 1, a non-optically activesubstance of the general formula (1) or (2) can also be produced by thesame method.

wherein R¹ to R³, R¹⁰ to R¹⁴, X, X′, j, and k are the same as thosedescribed above, B is a leaving group, and M represents an alkali metalor a hydrogen atom.

The alcohol (c) can be synthesized by a Diels-Alder reaction of thediene (a) having substituents and the alkyne (b) having a substituent.The reagent used is a metal complex such as[1,2-bis(diphenylphosphino)ethane]cobalt(II) dibromide,1,5-cyclooctadiene(naphthalene)rhodium(I) tetrafluoroborate,dichloro(1,4-diaza-1,3-diene)iron(II), ordichlorobis(tri-o-biphenylphosphite)nickel(II). A solvent used for theDiels-Alder reaction is not particularly limited, unless the reaction isadversely affected. Examples of the solvent include ethers such asdiethyl ether, tetrahydrofuran, and dioxane; aromatic hydrocarbons suchas toluene and xylene; halogen-containing hydrocarbon solvents such asdichloromethane and 1,2-dichloroethane; aprotic polar solvents such asacetonitrile, ethyl acetate, and acetone; and the like. Dichloromethaneor tetrahydrofuran is particularly preferable. The reaction temperatureof the Diels-Alder reaction is in a range of generally −20° C. to 100°C., and preferably 10° C. to 40° C., although it naturally variesdepending on the substrate used. In addition, the reaction time of theDiels-Alder reaction is generally 30 minutes to 30 hours, and preferably1 hour to 20 hours, although it naturally varies depending on thesubstrate used. Note that the Diels-Alder reaction is preferablyperformed in an inert gas such as nitrogen or argon.

Next, the hydroxyl group moiety of the alcohol (c) is converted to aleaving group such as a halogen atom, an alkanesulfonyloxy group, or anarenesulfonyloxy group, and thus the compound represented by the generalformula (d) is synthesized. The reagent used here is hydrogen chloride,thionyl chloride, sulfuryl chloride, oxalyl chloride, phosphorustrichloride, phosphorus pentachloride, hydrogen bromide, phosphorustribromide, phosphorus pentabromide, carbon tetrabromide,dimethylbromosulfonium bromide, thionyl bromide, hydrogen iodide,phosphorus triiodide, triphenyl phosphite methiodide, p-toluenesulfonylchloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride,trifluoromethanesulfonic anhydride, or the like. The reaction solvent isnot particularly limited, and examples thereof include ethers such asdiethyl ether, tetrahydrofuran, and dioxane; aromatic hydrocarbons suchas benzene, toluene, and xylene; halogen-containing hydrocarbon solventssuch as dichloromethane and 1,2-dichloroethane; aprotic polar solventssuch as N,N-dimethylformamide, acetonitrile, and dimethyl sulfoxide;alcohols such as methanol, ethanol, and 2-propanol; and the like.Dichloromethane, tetrahydrofuran, or toluene is particularly preferable.Note that, for some reaction systems, it is preferable to perform thisreaction in the presence of a base in an amount of 1 to 2 equivalents tothe reaction substrate. The reaction temperature is in a range ofgenerally −30° C. to 200° C., and preferably 10° C. to 100° C., althoughit naturally varies depending on the substrate used. In addition, thereaction time is generally 30 minutes to 30 hours, and preferably 1 hourto 20 hours, although it naturally varies depending on the substrateused. Note that the reaction is preferably performed in an inert gassuch as nitrogen or argon.

Next, a solvent used for synthesizing a compound represented by thegeneral formula (e) from the compound represented by the general formula(d) and a diamine compound is preferably an ether such as 1,4-dioxane;an aromatic hydrocarbon such as toluene, xylene, or mesitylene; ahalogen-containing aromatic hydrocarbon such as chlorobenzene; anaprotic polar solvent such as N,N-dimethylformamide or dimethylsulfoxide; or the like, and is particularly preferably dimethylsulfoxide, toluene, xylene, or mesitylene, although the solvent is notparticularly limited. In addition, the reaction can also be performed ina mixture solvent of an organic solvent with water by using water asanother solvent. Meanwhile, the base used for the reaction is preferablyan inorganic base such as sodium hydroxide, sodium hydrogen carbonate,sodium carbonate, potassium hydroxide, potassium hydrogen carbonate,potassium carbonate, lithium hydroxide, lithium hydrogen carbonate,lithium carbonate, cesium carbonate, magnesium hydroxide, magnesiumcarbonate, calcium hydroxide, or calcium carbonate; or a tertiaryorganic amine such as trimethylamine, triethylamine, triisopropylamine,tributylamine, or diisopropylethylamine, and is particularly preferablytriethylamine or diisopropylethylamine. The amount of the base used is0.2 to 2 equivalents, and preferably 1 to 1.5 equivalents to thecompound represented by the general formula (d). The reactiontemperature is, for example, 100° C. to 200° C., and preferably 100° C.to 160° C. The reaction time is 30 minutes to 30 hours, and preferably 1hour to 12 hours, although it varies depending on the reaction substrateused. The reaction is preferably performed in an inert gas such asnitrogen gas or argon gas. Moreover, an additive such as sodium iodide,potassium iodide, lithium iodide, sodium bromide, potassium bromide,lithium bromide, potassium chloride, or lithium chloride may be added.The additive is preferably potassium iodide or lithium iodide. Theamount of the additive is 0 to 10 equivalents, and preferably 0.1 to 1equivalents to the compound represented by the general formula (d).

From the compound of the general formula (e), the ruthenium-diaminecomplex (1) can be produced according to the description in Org. Lett. 9(2007), p. 4659, for example.

A solvent used for synthesizing the ruthenium dimer complex of thegeneral formula (2) from the compound of the general formula (e) andRuX′₃.nH₂O (for example, ruthenium (III) chloride or hydrate thereof) isnot particularly limited, and is an aliphatic alcohol such as2-propanol, n-butanol, 2-butanol, n-pentanol, 2-pentanol, 3-pentanol,3-methyl-1-butanol, cyclopentanol, 3-methoxy-1-propanol,2-methoxyethanol, 2-ethoxyethanol, 2-isopropoxyethanol, n-hexanol,3-methoxy-1-butanol, 3-methoxy-3-methyl-1-butanol, 2-hexanol, 3-hexanol,cyclohexanol, n-heptanol, 2-heptanol, 3-heptanol, cycloheptanol,n-octanol, 2-octanol, 3-octanol, 4-octanol, or cyclooctanol; an aromaticalcohol such as phenol, benzyl alcohol, 1-phenylethanol,2-phenylethanol, o-cresol, m-cresol, p-cresol, 2-methylbenzyl alcohol,3-methylbenzyl alcohol, or 4-methylbenzyl alcohol; a diol such asethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,2-butanediol,1,3-butanediol, 1,4-butanediol, ethylene glycol-n-butyl ether, ethyleneglycol-iso-butyl ether, or ethylene glycol-n-hexyl ether; a derivativethereof; or the like. One of these solvents may be used alone, or two ormore thereof may be used as a mixture. By using two or more solvents incombination, the boiling point of the solvent can be adjusted in adesired range, so that the reaction temperature can be controlled forthe reaction under reflux. For example, an alcohol with which a smallamount of water is mixed may be used. The amount of the compound of thegeneral formula (e) used is 1 to 20 equivalents, preferably 1 to 10equivalents, and more preferably 1 to 5 equivalents to ruthenium atoms.The amount of the solvent used is not particularly limited, as long asruthenium chloride or hydrate thereof can be dissolved therein at thereaction temperature. For example, the amount of the solvent is 2 to 50times volume (i.e., 2 to 50 mL of the solvent relative to 1 g ofruthenium chloride or hydrate thereof), preferably 2 to 30 times volume,and more preferably 5 to 20 times volume of ruthenium chloride orhydrate thereof. From the viewpoint of reaction efficiency, the reactiontemperature is 60° C. or above, and preferably 100° C. or above, andalso 200° C. or below, and preferably 160° C. or below, although itvaries depending on the solvent used.

A solvent used for synthesizing the ruthenium complex of the generalformula (1) from the ruthenium dimer complex of the general formula (2)is not particularly limited, and is a halogenated solvent such asmethylene chloride, dichloroethane, chloroform, or trifluoroethanol; anaromatic hydrocarbon such as toluene or xylene; an ether such asdiisopropyl ether or tetrahydrofuran; an alcohol such as methanol,ethanol, 2-propanol, n-butanol, 2-butanol, or n-pentanol; or the like.Dichloromethane or isopropanol is particularly preferable. One of thesesolvents may be used alone, or two or more thereof may be used as amixture. By using two or more solvents in combination, the boiling pointof the solvent can be adjusted in a desired range, so that the reactiontemperature can be controlled for the reaction under reflux. Forexample, an alcohol with which a small amount of water is mixed may beused. The base used here is an inorganic base such as sodium hydroxide,sodium hydrogen carbonate, sodium carbonate, potassium hydroxide,potassium hydrogen carbonate, potassium carbonate, lithium hydroxide,lithium hydrogen carbonate, lithium carbonate, cesium carbonate,magnesium hydroxide, magnesium carbonate, calcium hydroxide, or calciumcarbonate; an amine such as triethylamine, tripropylamine,tributylamine, pyridine, or triisopropylamine; or the like.Triethylamine is particularly preferable. The amount of the base used is0.2 to 2 equivalents, and preferably 1 to 1.5 equivalents to theruthenium atoms. The reaction time is 30 minutes to 20 hours, andpreferably 1 hour to 12 hours, although it varies depending on thereaction substrate used. The reaction is preferably performed in aninert gas such as nitrogen gas or argon gas.

By bringing the ruthenium complex of the general formula (1) in which Xis a halogen atom, a trifluoromethanesulfonyloxy group, ap-toluenesulfonyloxy group, a methanesulfonyloxy group, or abenzenesulfonyloxy group into contact with a hydrogen donor, thisruthenium complex can be easily converted to a ruthenium complex of thegeneral formula (1) in which X is a hydrogen atom. Here, as the hydrogendonor, those generally used as a hydrogen donor in a hydrogen transferreduction reaction, such as formic acid, salts thereof, isopropanol, andmetal hydrides including borohydride compounds, can be used. The amountof the hydrogen donor used only needs to be equimolar to the catalyst ormore in terms of hydride. In addition, hydrogen gas can also be used asthe hydrogen donor. In addition, a base used to achieve a basiccondition in this reaction is a tertiary organic amine such astrimethylamine, triethylamine, or triisopropylamine; an inorganic basesuch as LiOH, NaOH, KOH, or K₂CO₃; or a metal alkoxide such as sodiummethoxide or potassium methoxide.

In addition, the cationic ruthenium complex represented by the generalformula (1′) of the present invention can be obtained by, for example,by a method according to Scheme 2 below, i.e., by reacting the complex(1*) in which X is a halogen atom with a metal salt represented by M-Q.

Examples of the metal M in M-Q include silver (Ag), sodium (Na),potassium (K), lithium (Li), and the like. Q is alkanesulfonyloxy orarene sulfonyloxy such as trifluoromethanesulfonyloxy (TfO),p-toluenesulfonyloxy (TsO), methanesulfonyloxy (MsO), orbenzenesulfonyloxy (BsO), or the like. Alternatively, Q may be BF₄,SbF₆, CF₃COO, CH₃COO, PF₆, NO₃, ClO₄, SCN, OCN, ReO₄, MoO₄, BPh₄, B(C₆F₅)₄, B(3,5-(CF₃)₂C₆F₃)₄, or the like.

Examples of the metal salt represented by M-Q include AgOTf, AgOTs,AgOMs, AgOBs, AgBF₄, AgSbF₆, CF₃COOAg, CH₃COOAg, AgPF₆, AgNO₃, AgClO₄,AgSCN, AgOCN, AgReO₄, AgMoO₄, NaOTf, NaBF₄ NaSbF₆, CF₃COONa, CH₃COONa,NaPF₆, NaNO₃, NaClO₄, NaSCN, KOTf, KBF₄, KSbF₆, CF₃COOK, CH₃COOK, KPF₆,KNO₃, KClO₄, KSCN, KBPh₄, KB (C₆F₅)₄, KB(3,5-(CF₃)₂C₆F₃)₄, LiOTf, LiBF₄,LiSbF₆, CF₃COOLi, CH₃COOLi, LiPF₆, LiNO₃, LiClO₄, LiSCN, LiBPh₄, LiB(C₆F₅)₄, LiB(3,5-(CF₃)₂C₆F₃)₄, and the like.

The metal salt M-Q in Scheme 2 is used in an equimolar amount to theruthenium atoms or more. A solvent used in this case is not particularlylimited, and is an alcohol such as methanol, ethanol, or isopropanol; anaromatic hydrocarbon such as toluene or xylene; a halogenatedhydrocarbon such as dichloromethane or 1,2-dichloroethane; an aproticpolar solvent such as acetonitrile or N,N-dimethylformamide; an ethersuch as diethyl ether or tetrahydrofuran; or the like. Of thesesolvents, methanol is preferable.

The ruthenium complex of each of the general formulae (1*), (1′), and(2*) can be used as a catalyst for asymmetric reduction. The asymmetricreduction reaction may be performed by using the prepared rutheniumcomplex of the general formula (1*) or (1′) or the general formula (2*)as a catalyst for asymmetric reduction after isolation, or by directlyusing the reaction liquid in which the ruthenium complex is preparedwithout isolating the ruthenium complex (in situ method). Note that theruthenium dimer complex of the general formula (2*) is preferably usedafter isolation. The ruthenium complex of the general formula (1*),(1′), or (2*) can be isolated by a common crystallization approach suchas concentration of the reaction liquid or addition of a poor solventafter completion of the preparation reaction of the complex. Inaddition, when a hydrogen halide is by-produced in the preparation ofthe complex, a washing operation with water may be performed, ifnecessary. In addition, the conversion of the ruthenium complex of thegeneral formula (1) in which X is a halogen atom or the like to theruthenium complex of the general formula (1*) in which X is a hydrogenatom may be conducted in advance before the use for the asymmetricreduction reaction, or may be performed during the asymmetric reductionreaction.

The asymmetric reduction reactions include (i) reactions for preparingan optically active alcohol by reducing a carbonyl group of a carbonylcompound, and (ii) reactions for preparing an optically active amine byreducing an imino group of an imine compound, each being performed inthe presence of the ruthenium complex represented by the general formula(1*), (1′), or (2*) and a hydrogen donor. The hydrogen donor is notparticularly limited, as long as the hydrogen donor is one generallyused for a hydrogen transfer reduction reaction, such as formic acid, asalt thereof, or isopropanol, which is an alcohol having a hydrogen atomat an α-position of a carbon atom substituted with a hydroxyl group. Inaddition, hydrogen gas can also be used as the hydrogen donor. Inaddition, the asymmetric reduction reaction is preferably performed inthe presence of a base. The base is a tertiary organic amine such astrimethylamine, triethylamine, or triisopropylamine or an inorganic basesuch as LiOH, NaOH, KOH, or K₂CO₃. The base is preferably triethylamine.The base is used in an excessive amount relative to the rutheniumcomplex, and the amount is, for example, 1 to 100000 times of the amountof the ruthenium complex in terms of molar ratio. When triethylamine isused, triethylamine is preferably used in an amount 1 to 10000 times ofthe amount of the catalyst.

When formic acid is used as the hydrogen donor, an amine is preferablyused as the base. In this case, formic acid and the amine may be addedto the reaction system separately, or an azeotrope of formic acid andthe amine prepared in advance may be used.

In general, in the reaction, the hydrogen donor can be used as thereaction solvent, when the hydrogen donor is liquid. It is also possibleto use one of or a mixture of two or more of non-hydrogen-donatingsolvents such as toluene, tetrahydrofuran, acetonitrile,dimethylformamide, dimethyl sulfoxide, acetone, and methylene chlorideas an auxiliary solvent for dissolving the raw material. In a case wherea formate is used or the like, the reaction may also be performed in atwo-layer system in which water is used as an auxiliary solvent fordissolving the formate in combination with an organic solvent. In thiscase, a phase transfer catalyst may be used in combination in order toaccelerate the reaction. In addition, when hydrogen gas is used as thehydrogen donor, it is preferable to use an alcohol solvent such asmethanol, ethanol, or isopropanol.

The amount of the ruthenium complex, which serves as a catalyst, used isselected such that the molar ratio (S/C) of a substrate (S) (a carbonylcompound or an imine) to the ruthenium metal atoms (C) can be in a rangefrom 10 to 1000000, and preferably from 100 to 15000.

The amount of the hydrogen donor used is generally equimolar or more tothe carbonyl compound or the imine. When formic acid or a salt thereofis used as the hydrogen donor, the amount is preferably 1.5 times bymole or more. In addition, the amount is preferably 20 times by mole orless, and more preferably 10 times by mole or less. On the other hand,when the hydrogen donor is isopropanol or the like, the hydrogen donoris used in large excess relative to the substrate from the viewpoint ofthe reaction equilibrium, and the amount used is generally in a range of1000 times by mole or less.

The reaction temperature is not particularly limited, and is generally−20 to 100° C., and preferably 0 to 70° C. The reaction pressure is notparticularly limited, and is generally 0.5 to 2 atm, and preferablynormal pressure. In addition, when hydrogen gas is used, the reactionpressure is generally 5 MPa or less, and preferably 3 MPa or less. Thereaction time is 1 to 100 hours, and generally 2 to 50 hours, althoughit varies depending on the molar ratio (S/C).

After the reaction, the formed optically active substance can beseparated and purified by a common operation such as distillation,extraction, chromatography, or recrystallization.

EXAMPLES

Hereinafter, the present invention will be described in detail based onExamples. However, the present invention is not limited to theseExamples.

Note that, in the following Examples and the like, NMR spectra used foridentification of complexes and determination of purities thereof weremeasured with a Mercury Plus 300 4N model apparatus manufactured byVarian Technologies Japan Ltd., or Bruker BioSpin Avance III 500 System.For GC analysis, Chirasil-DEX CB (0.25 mm×25 m, 0.25 μm) (manufacturedby Varian, Inc.) or HP-1 (0.32 mm×30 m, 0.25 μm) (manufactured byAgilent Technologies, Inc.) was used. For HPLC analysis, YMC-Pack ProC18 (4.6×250 mm, 5 μm) (manufactured by YMC) or CHIRALPAK AS-H (4.6×250mm, 5 μm) was used. In addition, for MS measurement, JMS-T100 GCVmanufactured by JEOL Ltd. or LCMS-IT-TOF manufactured by ShimadzuCorporation was used.

In addition, the meanings of abbreviations in Examples are as follows.

-   THF: tetrahydrofuran-   Msdpen: N-methanesulfonyl-1,2-diphenylethylenediamine-   Tsdpen: N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine-   DIPEA: diisopropylethylamine

S/C represents a value represented by the number of moles of the ketoneor imine substrate/the number of moles of the catalyst.

Example 1 Production of 4-(4-methylcyclohexa-1,4-dienyl)butan-1-ol and4-(5-methylcyclohexa-1,4-dienyl) butan-1-ol

In 45 mL of THF, 1,2-bis(diphenylphosphino) ethane (0.77 g, 1.93 mmol),cobalt bromide 0.41 (0.41 g, 1.87 mmol), zinc iodide (1.19 g, 3.73mmol), and zinc (0.24 g, 3.67 mmol) were dissolved, followed by stirringat 70° C. for 15 minutes. After cooling to room temperature, isoprene(7.55 g, 110.83 mmol) was added. Then, 5-hexyn-1-ol (8.94 g, 91.09 mmol)was slowly added dropwise with cooling in a water bath. After stirringat 35° C. for 1 hour, the solvent was evaporated under reduced pressure,and the obtained residue was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1). Thus, 13.34 g of the titlecompounds, alcohols, were obtained as a colorless oily substance. Yield:88.10 (isomer ratio: 1,4 type/1,5 type=77/23). Note that the followingNMR spectrum data are those of the isomer mixture.

¹H-NMR (CDCl₃, 300 MHz): δ 5.61-5.57 (m, 2H′), 5.43-5.41 (m, 2H),3.67-3.63 (m, 2H+2H′), 2.58 (brs, 4H), 2.10 (brs, 4H′), 2.08 (t, J=6.9Hz, 2H′), 2.00 (t, J=7.2 Hz, 2H), 1.76 (s, 3H′), 1.67 (s, 3H), 1.61-1.43(m, 5H+5H′);

HRMS (ESI): calcd for C₁₁H₁₉O [M+H]+ 167.1430. found 167.1432

Example 2 Production of 4-(4-methylcyclohexa-1,4-dienyl)butyl4-methylbenzenesulfonate and 4-(5-methylcyclohexa-1,4-dienyl)butyl4-methylbenzenesulfonate

The alcohols (12.19 g, 73.32 mmol, isomer ratio: 1,4 type/1,5type=77/23) obtained in Example 1, triethylamine (8.90 g, 87.98 mmol),and 1-methylimidazole (7.22 g, 87.98 mmol) were dissolved in 10 mL oftoluene. With cooling in an ice-bath, a toluene solution (40 ml) ofp-toluenesulfonyl chloride (15.94 g, 83.58 mmol) was slowly addeddropwise, followed by stirring at room temperature for 1 hour. Tap waterwas added thereto, and the resultant layers were separated from eachother. The obtained organic layer was washed with 2 M hydrochloric acidand tap water. The solvent was evaporated under reduced pressure, andthe obtained residue was purified by silica gel column chromatography(hexane/ethyl acetate=20/1→4/1). Thus, 20.25 g of the title compounds,tosylates, were obtained as a colorless oily substance. Yield: 86.2%(isomer ratio: 1,4 type/1,5 type=77/23). Note that the following NMRspectrum data are those of the isomer mixture.

¹H-NMR (CDCl₃, 300 MHz): δ 7.80-7.77 (m, 2H+2H′), 7.36-7.33 (m, 2H+2H′),5.58-5.56 (m, 1H′), 5.51-5.49 (m, 1H′), 5.39-5.38 (m, 1H), 5.35-5.34 (m,1H), 4.05-4.01 (m, 2H+2H′), 2.53 (brs, 4H), 2.45 (s, 3H+3H′), 2.05 (brs,4H′), 1.99 (t, J=7.4 Hz, 2H′), 1.91 (t, J=7.4 Hz, 2H), 1.76 (s, 3H′),1.66 (s, 3H), 1.67-1.58 (m, 2H+2H′), 1.49-1.37 (m, 2H+2H′);

HRMS (ESI): calcd for C₁₈H₂₄O₃SNa [M+Na]+ 343.1338. found 343.1330

Example 3 Production of4-methyl-N-((1S,2S)-2-(4-(4-methylcyclohexa-1,4-dienyl)butylamino)-1,2-diphenylethyl)benzenesulfonamideand4-methyl-N-((1S,2S)-2-(4-(5-methylcyclohexa-1,4-dienyl)butylamino)-1,2-diphenylethyl)benzenesulfonamide

The tosylates (10.45 g, 32.61 mmol, isomer ratio: 1,4 type/1,5type=77/23) obtained in Example 2 were dissolved in 40 ml of toluene,and DIPEA (4.79 g, 32.61 mmol) and (S,S)-TsDPEN (11.95 g, 32.61 mmol)were added thereto, followed by stirring at 135° C. for 14 hours. Afterthat, the solvent was evaporated under reduced pressure, and theobtained residue was purified by silica gel column chromatography(hexane/ethyl acetate=2/1). Thus, 9.31 g of the title compounds wereobtained as a yellow oily substance. Yield: 55.5% (isomer ratio: 1,4type/1,5 type=77/23). Note that the following NMR spectrum data arethose of the isomer mixture.

¹H NMR (CDCl₃, 300 MHz): δ 7.38-7.36 (m, 2H+2H′), 7.14-7.12 (m, 3H+3H′),7.05-7.00 (m, 5H+5H′), 6.96-6.88 (m, 4H+4H′), 6.30 (brs, 1H+1H′),5.60-5.58 (m, 1H′), 5.53-5.51 (m, 1H′), 5.41-5.40 (m, 1H), 5.37-5.36 (m,1H), 4.24-4.22 (m, 1H+1H′), 3.60-3.58 (m, 1H+1H′), 2.55 (brs, 4H),2.46-2.37 (m, 1H+1H′), 2.34 (s, 3H+3H′), 2.32-2.23 (m, 1H+1H′), 2.01(brs, 4H′), 2.01-1.88 (m, 2H+2H′), 1.77 (s, 3H′), 1.67 (s, 3H),1.46-1.28 (m, 5H+5H′);

HRMS (ESI): calcd for C₃₂H₃₉N₂O₂S [M+H]+ 515.2727. found 515.2747

Example 4 Production of4-methyl-N-((1S,2S)-2-(4-(4-methylcyclohexa-1,4-dienyl)butylamino)-1,2-diphenylethyl)benzenesulfonamidehydrochloride and4-methyl-N-((1S,2S)-2-(4-(5-methylcyclohexa-1,4-dienyl)butylamino)-1,2-diphenylethyl)benzenesulfonamidehydrochloride

The amides (8.55 g, 16.61 mmol, isomer ratio: 1,4 type/1,5 type=77/23)obtained in Example 3 were dissolved in 33 ml of toluene. Underice-cooling, a 1 M hydrochloric acid methanolic solution (3.46 g, 33.22mmol) was added, followed by stirring at room temperature for 20minutes. After that, the solvent was evaporated under reduced pressure.Thus, 8.85 g of the title compounds, diamine hydrochlorides, wereobtained as a white solid. Yield: 96.7% (isomer ratio: 1,4 type/1,5type-77/23). Note that the following NMR spectrum data are those of theisomer mixture.

¹H-NMR (d₆-DMSO, 300 MHz) δ:

9.61 (brs, 1H+1H′), 9.15 (brs, 1H+1H′), 8.85 (d, 1H+1H′), 7.29-6.79 (m,14H+14H′), 5.55 (m, 1H′), 5.48 (m, 1H′), 5.36 (m, 1H), 5.31 (m, 1H),4.82 (m, 1H+1H′), 4.54 (m, 1H+1H′), 2.66 (brs, 4H), 2.20 (s, 3H+3H′),1.99 (brs, 4H′), 1.98-1.90 (m, 2H′), 1.90-1.82 (m, 2H), 1.71 (s, 3H′),1.70-1.52 (m, 2H+2H′), 1.61 (s, 3H), 1.38-1.18 (m, 2H+2H′);

HRMS (ESI): calcd for C₃₂H₃₉N₂O₂S [M-Cl]+515.2727. found 515.2728

Example 5 Production ofN-[(1S,2S)-1,2-diphenyl-2-(4-(4-methylphenyl)butylamino)-ethyl]-4-methylbenzenesulfonamideammonium chloride ruthenium dimer andN-[(1S,2S)-1,2-diphenyl-2-(4-(3-methylphenyl)butylamino)-ethyl]-4-methylbenzenesulfonamideammonium chloride ruthenium dimer

The hydrochlorides (7.42 g, 13.46 mmol, isomer ratio: 1,4 type/1,5type=77/23) obtained in Example 4 and ruthenium trichloride.trihydrate(3.20 g, 12.25 mmol) were dissolved in a mixture solvent of 110 ml of3-methoxypropanol and 37 ml of water, followed by stirring at 120° C.for 1 hour. The solvent was evaporated under reduced pressure, anddiethyl ether was added to the obtained residue, followed by stirring atroom temperature for 15 minutes. The precipitated crystals werefiltered. Thus, 10.15 g of the title compounds, ruthenium dimers, wereobtained. Yield: 52.3%. The following NMR spectrum data are those of themajor product (1,4 type).

¹H NMR (d₆-DMSO, 500 MHz): δ 9.61 (brs, 2H), 9.11 (brs, 2H), 8.78 (d,J=9.1 Hz, 2H), 7.30-6.88 (m, 28H), 6.82-6.81 (m, 8H), 4.83 (m, 2H), 4.56(m, 2H), 2.71 (brs, 4H), 2.35 (t, J=7.5 Hz, 4H), 2.22 (s, 6H), 2.10 (s,6H), 1.80-1.60 (m, 4H), 1.60-1.42 (m, 4H);

HRMS (FD): calcd for C₃₂H₃₅ClN₂O₂RuS [M/2-2HCl]+ 648.1156. found648.1182

Example 6 Production ofN-[(1S,2S)-1,2-diphenyl-2-(4-(4-methylphenyl)butylamino)-ethyl]-4-methylbenzenesulfonamideammonium chloride ruthenium monomer andN-[(1S,2S)-1,2-diphenyl-2-(4-(3-methylphenyl)butylamino)-ethyl]-4-methylbenzenesulfonamideammonium chloride ruthenium monomer

The ruthenium dimers (9.12 g, 6.32 mmol) obtained in Example 5 weredissolved in 155 ml of 2-propanol, and triethylamine (2.53 g, 25.29mmol) was added thereto, followed by stirring at 60° C. for 1 hour.After that, the solvent was evaporated under reduced pressure, and theobtained residue was purified by silica gel chromatography(chloroform/methanol=20/1). Thus, 6.77 g of the title compounds,ruthenium monomers, were obtained. Yield: 82.6% (the chemical puritybased on HPLC was 97.2%). The following NMR spectrum data are those ofthe major product (1,4 type).

¹H NMR (CD₂Cl₂, 500 MHz): δ 7.17 (d, J=7.9 Hz, 2H), 7.10-7.05 (m, 3H),6.86 (d, J=7.9 Hz, 2H), 6.82-6.79 (m, 1H), 6.74 (d, J=6.4 Hz, 2H), 6.68(dd, J=7.9 Hz, 2H), 6.56 (d, J=7.9 Hz, 2H), 6.18 (d, J=5.6 Hz, 1H), 5.55(d, J=6.3 Hz, 1H), 5.35 (d, J=6.3 Hz, 1H), 5.29 (d, J=5.6 Hz, 1H),4.73-4.70 (m, 1H), 3.97 (d, J=11.0 Hz, 1H), 3.81 (dd, J=11.0, 12.2 Hz,1H), 3.52-3.47 (m, 1H), 3.13-3.07 (m, 1H), 2.85-2.81 (m, 1H), 2.75-2.69(m, 1H), 2.44 (s, 3H), 2.26 (s, 3H), 2.28-2.17 (m, 1H), 2.15-2.04 (m,1H), 1.96-1.88 (m, 1H), 1.67-1.60 (m, 1H);

HRMS (ESI): calcd for C₃₂H₃₆ClN₂O₂RuS [M+H]+ 649.1224. found 649.1224

Example 7 Production ofN-((1S,2S)-2-(4-(4-methylcyclohexa-1,4-dienyl)butylamino)-1,2-diphenylethyl)methanesulfonamideandN-((1S,2S)-2-(4-(5-methylcyclohexa-1,4-dienyl)butylamino)-1,2-diphenylethyl)methanesulfonamide

The tosylates (5.11 g, 15.95 mmol) obtained in Example 2 were dissolvedin 20 ml of toluene, and DIPEA (2.05 g, 15.95 mmol) and (S,S)-MsDPEN(4.63 g, 15.95 mmol) were added thereto, followed by stirring at 135° C.for 16 hours. After that, the solvent was evaporated under reducedpressure, and the obtained residue was purified by silica gel columnchromatography (hexane/ethyl acetate=2/1). Thus, 5.72 g of the titlecompounds, diamines, were obtained as a yellow oily substance. Yield:81.8% (isomer ratio: 1,4 type/1,5 type=77/23). Note that the followingNMR spectrum data are those of the mixture of the two isomers.

¹H NMR (CDCl₃, 300 MHz): δ 7.26-7.19 (m, 10H+10H′), 6.23 (brs, 1H+1H′),5.59-5.58 (m, 1H′), 5.52-5.51 (m, 1H′), 5.40 (m, 1H), 5.36 (m, 1H),4.47-4.44 (m, 1H+1H′), 3.75-3.72 (m, 1H+1H′), 2.55 (brs, 4H), 2.46-2.37(m, 1H+1H′), 2.34 (s, 3H+3H′), 2.32-2.23 (m, 1H+1H′), 2.01 (brs, 4H′),2.01-1.88 (m, 2H+2H′), 1.77 (s, 3H′), 1.67 (s, 3H), 1.46-1.28 (m,5H+5H′);

HRMS (ESI): calcd for C₂₆H₃₅N₂O₂S [M+H]+ 439.2414. found 439.2409

Example 8 Production ofN-((1S,2S)-2-(4-(4-methylcyclohexa-1,4-dienyl)butylamino)-1,2-diphenylethyl)methanesulfonamidehydrochloride andN-((1S,2S)-2-(4-(5-methylcyclohexa-1,4-dienyl)butylamino)-1,2-diphenylethyl)methanesulfonamidehydrochloride

The diamines (5.11 g, 11.65 mmol) obtained in Example 7 were dissolvedin 20 ml of toluene. Under ice-cooling, a 1 M hydrochloric acidmethanolic solution (2.43 g, 23.30 mmol) was added thereto, followed bystirring at room temperature for 20 minutes. After that, the solvent wasevaporated under reduced pressure. Thus, 5.14 g of the title compounds,diamine hydrochlorides, were obtained as a white solid. Yield: 92.9%(isomer ratio: 1,4 type/1,5 type=77/23). Note that the following NMRspectrum data are those of the mixture of the two isomers.

¹H-NMR (d₆-DMSO, 300 MHz) δ:

9.94 (brs, 1H+1H′), 9.08 (brs, 1H+1H′), 8.34 (d, 1H+1H′), 7.39-7.00 (m,10H+10H′), 5.54 (m, 1H′), 5.47 (m, 1H′), 5.35 (m, 1H), 5.30 (m, 1H),4.90 (m, 1H+1H′), 4.56 (m, 1H+1H′), 2.72-2.56 (m, 6H+2H′), 2.47 (s,3H+3H′), 1.98 (brs, 4H′), 1.93 (t, J=6.9 Hz, 2H′), 1.85 (t, J=7.2 Hz,2H), 1.71 (s, 3H′), 1.70-1.52 (m, 2H+2H′), 1.61 (s, 3H), 1.38-1.18 (m,2H+2H′);

HRMS (ESI): calcd for C₂₆H₃₅N₂O₂S [M-Cl]+ 439.2414. found 439.2422

Example 9 Production ofN-[(1S,2S)-1,2-diphenyl-2-(4-(4-methylphenyl)butylamino)-ethyl]-methanesulfonamideammonium chloride ruthenium dimer andN-[(1S,2S)-1,2-diphenyl-2-(4-(3-methylphenyl)butylamino)-ethyl]-methanesulfonamideammonium chloride ruthenium dimer

The diamine hydrochlorides (4.05 g, 8.52 mmol) obtained in Example 8 andruthenium trichloride.trihydrate (2.03 g, 7.76 mmol) were dissolved in amixture solvent of 60 ml of 3-methoxypropanol and 19 ml of water,followed by stirring at 120° C. for 1 hour. The solvent was evaporatedunder reduced pressure, and diethyl ether was added to the obtainedresidue, followed by stirring at room temperature for 15 minutes. Theprecipitated crystals were filtered. Thus, 5.49 g of the titlecompounds, ruthenium dimers, were obtained. Yield: 49.9%. The followingNMR spectrum data are those of the major product (1,4 type).

¹H NMR (d₆-DMSO, 500 MHz): δ 9.87 (brs, 2H), 9.04 (brs, 2H), 8.27 (d,J=9.4 Hz, 2H), 7.39-7.01 (m, 20H), 5.76-5.73 (m, 8H), 4.91 (m, 2H), 4.59(m, 2H), 2.70 (brs, 4H), 2.62 (s, 6H), 2.35 (t, J=7.7 Hz, 4H), 2.09 (s,6H), 1.80-1.60 (m, 4H), 1.60-1.41 (m, 4H);

HRMS (FD): calcd for C₂₆H₃₁ClN₂O₂RuS [M/2-2HCl]+ 572.0841. found572.0863

Example 10 Production ofN-[(1S,2S)-1,2-diphenyl-2-(4-(4-methylphenyl)butylamino)-ethyl]-methanesulfonamideammonium chloride ruthenium monomer andN-[(1S,2S)-1,2-diphenyl-2-(4-(3-methylphenyl)butylamino)-ethyl]-methanesulfonamideammonium chloride ruthenium monomer

The ruthenium dimers (4.49 g, 3.48 mmol) of Example 9 were dissolved in85 ml of 2-propanol, and triethylamine (1.45 g, 13.92 mmol) was addedthereto, followed by stirring at 60° C. for 1 hour. After that, thesolvent was evaporated under reduced pressure, and the obtained residuewas purified by silica gel chromatography (chloroform/methanol=20/1).Thus, 3.38 g of the title compounds, ruthenium monomers, were obtained.Yield: 69.3% (the chemical purity based on HPLC was 98.2%). Thefollowing NMR spectrum data are those of the major product (1,4 type).

¹H NMR (CD₂Cl₂, 500 MHz): δ 7.17-7.13 (m, 3H), 7.10-7.07 (m, 3H),6.97-6.95 (m, 2H), 6.85-6.83 (m, 2H), 5.84 (d, J=5.5 Hz, 1H), 5.51 (d,J=6.1 Hz, 1H), 5.46 (d, J=6.1 Hz, 1H), 5.38 (d, J=5.5 Hz, 1H), 4.41 (m,1H), 4.01 (d, J=10.7 Hz, 1H), 3.86 (dd, J=10.7, 12.2 Hz, 1H), 3.43-3.38(m, 1H), 3.12-3.07 (m, 1H), 2.80-2.71 (m, 2H), 2.47 (s, 3H), 2.37 (s,3H), 2.25-2.17 (m, 1H), 2.11-2.02 (m, 1H), 1.98-1.90 (m, 1H), 1.77-1.68(m, 1H);

HRMS (ESI): calcd for C₂₆H₃₂ClN₂O₂RuS [M+H]+ 573.0911. found 573.0912

Example 11 Production of 4-(4,5-dimethylcyclohexa-1,4-dienyl)butan-1-ol

In 40 mL of THF, 1,2-bis(diphenylphosphino)ethane (800 mg, 2.00 mmol),cobalt bromide (437 mg, 2.00 mmol), zinc iodide (1.28 g, 4.00 mmol), andzinc (260 mg, 4.00 mmol) were dissolved, followed by stirring at 70° C.for 15 minutes. After cooling to room temperature,2,3-dimethyl-1,3-butadiene (9.86 g, 120 mmol) was added. Then,5-hexyn-1-ol (9.8 g, 100 mmol) was slowly added dropwise with cooling ina water bath. After stirring at 35° C. for 1 hour, the solvent wasevaporated under reduced pressure, and the obtained residue was purifiedby silica gel column chromatography (hexane/ethyl acetate=3/1). Thus,11.5 g of the title compound, an alcohol, was obtained as a colorlessoily substance. Yield: 63.4%.

¹H NMR (CDCl₃, 300 MHz): δ 5.56-5.41 (m, 1H), 3.67-3.63 (m, 2H),2.61-2.48 (m, 2H), 2.11-1.98 (m, 3H), 1.63 (s, 6H), 1.79-1.46 (m, 4H),1.28 (brs, 1H)

Example 12 Production of 4-(4,5-dimethylcyclohexa-1,4-dienyl)butyl4-methylbenzenesulfonate

In 55 mL of toluene, 4-(4,5-dimethylcyclo-1,4-diene)butan-1-ol (11.0 g,61.0 mmol), triethylamine (7.40 g, 73.08 mmol), and 1-methylimidazole(6.0 g, 73.0 mmol) were dissolved. With cooling in an ice-bath, atoluene solution (40 ml) of p-toluenesulfonyl chloride (13.9 g, 73.1mmol) was slowly added dropwise, followed by stirring at roomtemperature for 1 hour. Tap water was added thereto, and the resultantlayers were separated from each other. The obtained organic layer waswashed with 2 M hydrochloric acid and tap water. The solvent wasevaporated under reduced pressure, and the obtained residue was purifiedby silica gel column chromatography (hexane/ethyl acetate=20/1→4/1).Thus, 16.3 g of the title compound, a tosylate, was obtained. Yield:80%.

¹H NMR (CDCl₃, 300 MHz): δ 7.80-7.77 (d, 2H), 7.36-7.33 (d, 2H),5.40-5.28 (m, 1H), 4.05-4.00 (m, 2H), 2.53 (brs, 2H), 2.45 (s, 3H),2.05-1.89 (m, 3H), 1.79-1.74 (m, 3H), 1.67 (s, 6H), 1.60-1.41 (m, 2H)

Example 13 Production of4-methyl-N-((1S,2S)-2-(4-(4,5-dimethylcyclohexa-1,4-dienyl)butylamino)-1,2-diphenylethyl)benzenesulfonamidehydrochloride

In 30 ml of toluene,4-(4,5-dimethylcyclo-1,4-diene)butyl-p-toluenesulfonate (3.3 g, 9.87mmol) was dissolved, and DIPEA (1.40 g, 10.79 mmol) and (S,S)-TsDPEN(3.3 g, 90.0 mmol) were added thereto, followed by stirring at 130° C.for 14 hours. After that, the solvent was evaporated under reducedpressure, and the obtained residue was purified by silica gel columnchromatography (hexane/ethyl acetate=2/1). Then, a 1 M hydrochloric acidmethanolic solution was added under ice-cooling, followed by stirring atroom temperature for 20 minutes. After that, the solvent was evaporatedunder reduced pressure. Thus, 2.47 g of the title compound, a diaminehydrochloride, was obtained as a white solid. Yield: 44.3%.

¹H NMR (DMSO-d₆, 300 MHz): δ 9.80 (brs, 1H), 9.22 (brs, 1H), 9.01 (brs,1H), 7.29-7.21 (m, 7H), 6.99-6.82 (m, 7H), 5.40-5.28 (m, 1H), 4.90-4.84(m, 1H), 2.63 (brs, 2H), 2.40 (brs, 2H), 2.21 (s, 3H), 1.99-1.89 (m,2H), 1.75-1.62 (m, 2H), 1.58 (s, 6H), 1.60-1.41 (m, 2H)

HRMS (ESI): calcd for C₃₃H₄₁N₂O₂S [M-Cl]+529.2892. found 529.2892

Example 14 Production ofN-[(1S,2S)-1,2-diphenyl-2-(4-(3,4-dimethylphenyl)butylamino)-ethyl]-4-methylbenzenesulfonamideammonium chloride ruthenium dimer

In a mixture solvent of 35 ml of 2-methoxyethanol and 3.7 ml of water,4-methyl-N-((1S,2S)-2-(4-(4,5-dimethylcyclohexa-1,4-dienyl)butylamino)-1,2-diphenylethyl)benzenesulfonicacid hydrochloride (1.0 g, 1.77 mmol) and rutheniumtrichloride.trihydrate (3.86 mg, 1.45 mmol) were dissolved, followed bystirring at 120° C. for 1 hour. The solvent was evaporated under reducedpressure, and diethyl ether was added to the obtained residue, followedby stirring at room temperature for 15 minutes. The precipitatedcrystals were filtered. Thus, 1.39 g of a ruthenium dimer was obtained.Yield: 82.5%.

¹H NMR (DMSO-d₆, 300 MHz): δ 9.80 (brs, 1H), 9.22 (brs, 1H), 8.91 (brs,1H), 7.28-7.19 (m, 7H), 6.98 (d (J=8 Hz), 2H), 6.99-6.82 (m, 7H),5.40-5.28 (m, 1H), 4.90-4.84 (m, 1H), 2.63 (brs, 2H), 2.40 (brs, 2H),2.21 (s, 3H), 1.99-1.89 (m, 2H), 1.75-1.62 (m, 2H), 1.58 (s, 6H),1.60-1.41 (m, 2H)

Example 15 Production ofN-[(1S,2S)-1,2-diphenyl-2-(4-(3,4-dimethylphenyl)butylamino)-ethyl]-4-methylbenzenesulfonamideammonium chloride ruthenium monomer

The ruthenium dimer (870 mg, 1.27 mmol) obtained in Example 14 wasdissolved in 60 ml of 2-propanol, and triethylamine (514 mg, 5.07 mmol)was added thereto, followed by stirring at 60° C. for 1 hour. Afterthat, the solvent was evaporated under reduced pressure, and theobtained residue was purified by silica gel chromatography(chloroform/methanol=20/1). Thus, 500 mg of the title compound, aruthenium monomer, was obtained. Yield: 42.7%. HRMS (ESI): calcd forC₃₃H₃₈ClN₂O₂RuS [M+H]+ 663.1381. found 663.1371

Example 16 Hydrogen transfer reaction to acetophenone as substrate usingN-[(1S,2S)-1,2-diphenyl-2-(4-(4-methylphenyl)butylamino)-ethyl]-4-methylbenzenesulfonamideammonium chloride ruthenium monomer (hereinafter,RuCl(Tol-C4-teth-(S,S)-Tsdpen))

In a 25-ml Schlenk tube, 4.5 mg (0.00694 mmol, S/C=1000) of the complex,RuCl(Tol-C4-teth-(S,S)-Tsdpen), produced in Example 6, acetophenone(0.82 g, 6.86 mmol), and 3.4 ml of a formic acid-triethylamine (5:2)azeotrope were mixed with each other, and the reaction was allowed toproceed at 60° C. for 7 hours. GC analysis of the reaction liquid showedthat (S)-1-phenylethanol was formed with a conversion of 99.5% and 96.5%ee.

Example 17 Hydrogen transfer reaction to acetophenone as substrate usingN-[(1S,2S)-1,2-diphenyl-2-(4-(4-methylphenyl)butylamino)-ethyl]-4-methylbenzenesulfonamideammonium chloride ruthenium dimer

In a 25-ml Schlenk tube, 4.9 mg (0.00339 mmol, S/C=1000) of theruthenium dimer complex produced in Example 5, acetophenone (0.82 g,6.86 mmol), and 3.4 ml of a formic acid-triethylamine (5:2) azeotropewere mixed with each other, and the reaction was allowed to proceed at60° C. for 5 hours. GC analysis of the reaction liquid showed that(S)-1-phenylethanol was formed with a conversion of 98.9% and 96.6% ee.

Example 18 Hydrogen transfer reaction to acetophenone as substrate usingN-[(1S,2S)-1,2-diphenyl-2-(4-(4-methylphenyl)butylamino)-ethyl]-methanesulfonamideammonium chloride ruthenium monomer (hereinafter,RuCl(Tol-C4-teth-(S,S)-Msdpen))

In a 25-ml Schlenk tube, the complex, RuCl(p-Tol-C4-teth-(S,S)-Msdpen),produced in Example 10 (4.0 mg, 0.00694 mmol, S/C=1000), acetophenone(0.82 g, 6.86 mmol), and 3.4 ml of a formic acid-triethylamine (5:2)azeotrope were mixed with each other, and the reaction was allowed toproceed at 60° C. for 7 hours. GC analysis of the reaction liquid showedthat (S)-1-phenylethanol was formed with a conversion of 99.3% and 94.8%ee.

Example 19 Hydrogen transfer reaction to acetophenone as substrate usingN-[(1S,2S)-1,2-diphenyl-2-(4-(4-methylphenyl)butylamino)-ethyl]-methanesulfonamideammonium chloride ruthenium dimer

In a 25-ml Schlenk tube, 4.4 mg (0.00341 mmol, S/C=1000) of theruthenium dimer complex produced in Example 9, acetophenone (0.82 g,6.86 mmol), and 3.4 ml of a formic acid-triethylamine (5:2) azeotropewere mixed with each other, and the reaction was allowed to proceed at60° C. for 5 hours. GC analysis of the reaction liquid showed that(S)-1-phenylethanol was formed with a conversion of 99.2% and 95.0% ee.

Comparative Example 1 Hydrogen transfer reaction to acetophenone assubstrate using RuCl((S,S)-Tsdpen)(mesitylene)

In a 15-ml Schlenk tube, 6.2 mg (0.01 mmol, S/C=500) ofRuCl((S,S)-Tsdpen)(mesitylene), 0.67 ml (0.67 g, 5.0 mmol) ofacetophenone, and 2.5 ml of a formic acid-triethylamine (5:2) azeotropewere mixed with each other. After purging with nitrogen, the reactionwas allowed to proceed at 60° C. for 24 hours. GC analysis of thereaction liquid showed that (S)-1-phenylethanol was formed with aconversion of 52.3% and 93.0% ee.

Examples 20 to 35 and Comparative Examples 2 to 8

As Examples 20 to 35, hydrogen transfer reactions to ketones shown inTables 1, 2, and 3 below were conducted by the same operation as inExamples 16 and 18. In these reactions, the catalyst ratios (S/C) wereas shown in the tables, the reaction temperature was 60° C., and aformic acid-triethylamine (5:2) azeotrope was used as a hydrogen sourcein such an amount that the concentration of the substrate was 2 mol/L.The conversions and the optical purities were determined by analyzingthe reaction liquids by GC after predetermined periods.

In addition, as Comparative Examples, results of reactions in which RuCl((S,S)-Tsdpen) (mesitylene) was used in the same manner are also shownin each table. Note that, in these tables, conv. represents theconversion of the ketone substrate, selec. represents the selectivityfor the target product, % ee represents the optical purity, and S/Crepresents a value represented by the number of moles of the ketonesubstrate/the number of moles of the catalyst.

TABLE 1           Ru complex/ketone substrate

Ex. 20 to 22 S/C = 1000, 5 h S/C = 1000, 8 h S/C = 1000, 24 h RuCl(Tol-C4-teth-(S,S)- 98.7% conv. 99.1% conv. 99.8% conv. Tsdpen 89.8% ee83.6% ee 92.4% ee Ex. 23 to 25 S/C = 1000, 5 h S/C = 1000, 8 h S/C =1000, 24 h RuCl (Tol-C4-teth-(S,S)- 99.2% conv. 99.5% conv. 96.8% conv.Msdpen 89.3% ee 88.9% ee 89.0% ee Comp. Ex. 2 to 4 S/C = 500, 5 h S/C =500, 8 h S/C = 500, 24 h RuCl ((S,S)-Tsdpen)  7.6% conv.  3.4% conv.20.8% conv. (mesitylene) 49.6% ee 14.8% ee 86.6% ee

TABLE 2           Ru complex/ketone substrate

Ex. 26 to 28 S/C = 1000, 2 h S/C = 1000, 1 h S/C = 1000, 7 h RuCl(Tol-C4-teth-  100% conv.  100% conv. 99.0% conv. (S,S)-Tsdpen 81.4% ee(81.6% selec.) 93.6% ee 96.9% ee Ex. 29 to 31 S/C = 1000, 2 h S/C =1000, 1 h S/C = 1000, 7 h RuCl (Tol-C4-teth-  100% conv. 98.7% conv.99.0% conv. (S,S)-Msdpen 80.5% ee (72.5% selec.) 93.6% ee 95.2% ee Comp.Ex. 5 to 7 S/C = 500, 2 h S/C = 500, 5 h S/C = 500, 24 h RuCl((S,S)-Tsdpen)   0% conv. 97.7% conv. 53.2% conv. (mesitylene)   0% ee(66.0% selec.) 93.0% ee 90.9% ee

TABLE 3             Ru complex/ketone substrate

Ex. 32 to 34 S/C = 1000 S/C = 1000 S/C = 1000 RuCl (Tol-C4-teth-  5 h 24h  7 h (S,S)-Tsdpen 99.0% conv. 88.6% conv. 51.0% conv. 94.6% ee 81.1%ee 94.3% ee Ex. 35 to 37 S/C = 1000 S/C = 1000 S/C = 1000 RuCl(Tol-C4-teth-  5 h 24 h  7 h (S,S)-Msdpen 98.8% conv. 98.7% conv. 57.3%conv. 92.9% ee 95.3% ee 96.1% ee Comp. Ex. 8 to 10 S/C = 500 S/C = 500S/C = 500 RuCl ((S,S)-Tsdpen) 24 h 24 h 24 h (mesitylene) 28.1% conv.15.0% conv.  1.9% conv. 90.6% ee 65.8% ee 51.5% ee

Moreover, as Comparative Examples, results of hydrogen transferreactions in which three known complexes shown below were used are alsoshown.

N-[(1S,2S)-1,2-diphenyl-2-(3-(4-methylphenyl)propylamino)-ethyl]-4-methylbenzenesulfonamideammonium chloride ruthenium monomer andN-[(1S,2S)-1,2-diphenyl-2-(3-(3-methylphenyl)propylamino)-ethyl]-4-methylbenzenesulfonamideammonium chloride ruthenium monomer (hereinafter, referred to asRuCl(Tol-C3-teth-(S,S)-Tsdpen))

HRMS (ESI): calcd for C₃₁H₃₄ClN₂O₂RuS [M+H]+ 635.1072. found 635.1041

N-[(1S,2S)-1,2-diphenyl-2-(4-phenylbutylamino)-ethyl]-4-methylbenzenesulfonamideammonium chloride ruthenium monomer (hereinafter, referred to as RuCl(benz-C4-teth-(S,S)-Tsdpen))

HRMS (ESI): calcd for C₃₁H₃₄ClN₂O₂RuS [M+H]+ 635.1072. found 635.1047

N-[(1S,2S)-1,2-diphenyl-2-(4-phenylpropylamino)-ethyl]-4-methylbenzenesulfonamideammonium chloride ruthenium monomer (hereinafter, referred to asRuCl(benz-C3-teth-(S,S)-Tsdpen))

RuCl(Tol-C3-teth-(S,S)-Tsdpen) and RuCl(benz-C4-teth-(S,S)-Tsdpen) wereproduced by the method according to Scheme 1. Meanwhile,RuCl(benz-C3-teth-(S,S)-Tsdpen) was purchased from STREM CHEMICALS.

Comparative Example 11 Hydrogen transfer reaction to2′-fluoroacetophenone as substrate using RuCl(Tol-C3-teth-(S,S)-Tsdpen)

In a 20-ml Schlenk tube, RuCl(Tol-C3-teth-(S,S)-Tsdpen) (4.20 mg,0.00662 mmol, S/C=1000), 2′-fluoroacetophenone (0.91 g, 6.60 mmol), and3.4 ml of a formic acid-triethylamine (5:2) azeotrope were mixed witheach other, and the reaction was allowed to proceed at 60° C. for 5hours. GC analysis of the reaction liquid showed that(S)-1-(2-fluorophenyl)ethanol was formed with a conversion of 99.2% and82.0% ee.

Comparative Example 12 Hydrogen transfer reaction to2′-fluoroacetophenone as substrate using RuCl(benz-C4-teth-(S,S)-Tsdpen)

In a 20-ml Schlenk tube, RuCl(benz-C3-teth-Tsdpen) (4.20 mg, 0.00662mmol, S/C=1000), 2′-fluoroacetophenone (0.91 g, 6.60 mmol), and 3.4 mlof a formic acid-triethylamine (5:2) azeotrope were mixed with eachother, and the reaction was allowed to proceed at 60° C. for 5 hours. GCanalysis of the reaction liquid showed that(S)-1-(2-fluorophenyl)ethanol was formed with a conversion of 99.1% and83.5% ee.

Comparative Example 13 Hydrogen transfer reaction to2′-fluoroacetophenone as substrate using RuCl(benz-C3-teth-(S,S)-Tsdpen)

In a 20-ml Schlenk tube, RuCl(benz-C4-teth-Tsdpen) (4.10 mg, 0.00661mmol, S/C=1000), 2′-fluoroacetophenone (0.91 g, 6.60 mmol), and 3.4 mlof a formic acid-triethylamine (5:2) azeotrope were mixed with eachother, and the reaction was allowed to proceed at 60° C. for 5 hours. GCanalysis of the reaction liquid showed that(S)-1-(2-fluorophenyl)ethanol was formed with a conversion of 99.2% and83.6% ee.

Comparative Examples 14 to 22

Hydrogen transfer reactions to ketones shown in Table 4 below wereconducted by the same operation as in Comparative Examples 11 to 13.Table 4 shows results thereof.

TABLE 4           Ru complex/ketone substrate

Comp. Ex. S/C = 1000 S/C = 1000 S/C = 1000 14 to 16 8 h 24 h 2 hRuCl(Tol-C3-teth- 99.5% conv. 99.8% conv.  100% conv. (S,S)-Tsdpen 73.8%ee 83.7% ee 70.7% ee Comp. Ex. S/C = 1000 S/C = 1000 S/C = 1000 17 to 198 h 24 h 2 h RuCl(benz-C4-teth- 99.5% conv. 99.1% conv.  100% conv.(S,S)-Tsdpen 78.2% ee 78.9% ee 68.8% ee Comp. Ex. S/C = 1000 S/C = 1000S/C = 1000 20 to 22 8 h 24 h 2 h RuCl(benz-C3-teth- 99.7% conv. 99.6%conv.  100% conv. (S,S)-Tsdpen) 68.5% ee 69.8% ee 60.6% ee

The results of Comparative Examples 11 to 22 showed that the complexesof the present invention were better in stereoselectivity and achievedhigher enantiomeric excesses than the known complexes,RuCl(Tol-C3-teth-(S,S)-Tsdpen), RuCl(benz-C4-teth-(S,S)-Tsdpen), andRuCl(benz-C3-teth-(S,S)-Tsdpen). The ruthenium complexes of the presentinvention are extremely useful, because the ruthenium complexes make itpossible to obtain target substances with high optical purities and highyields in hydrogen transfer reactions and hydrogenation reactions.

Example 38 Hydrogen transfer reaction to(E)-N-(3,4-dihydronaphthalene-1(2H)-ylidene)-1-phenylmethanamine usingRuCl(Tol-C4-teth-(S,S)-Tsdpen)

In a 20-ml Schlenk tube, 3.7 mg (0.0057 mmol, S/C=300) ofRuCl(Tol-C4-teth-(S,S)-Tsdpen), 0.40 g (1.70 mmol) of the imine in thetitle, 3.4 ml of dichloromethane, and 0.86 ml of a formicacid-triethylamine (5:2) azeotrope were mixed with each other, and thereaction was allowed to proceed at 30° C. for 20 hours. GC analysis ofthe reaction liquid showed that optically activeN-benzyl-1,2,3,4-tetrahydronaphthalene-1-amine was formed with aconversion of 100% and 75.2% ee.

Example 39 Asymmetric hydrogenation of 4-chromanone usingRuCl(Tol-C4-teth-(S,S)-Tsdpen)

In a 100-ml autoclave, 3.1 mg (0.00478 mmol, S/C=1000) ofRuCl(Tol-C4-teth-(S,S)-Tsdpen) was placed, followed by purging withnitrogen. Subsequently, 0.72 g (5.0 mmol) of 4-chromanone and 4.4 ml ofmethanol were added thereto, and hydrogen was introduced to a pressureof 3.0 MPa, followed by stirring at 60° C. for 19 hours. The result ofGC analysis of the reaction liquid showed that (S)-4-chromanol wasobtained with a conversion of 100% and an optical purity of 97.9% ee.

Example 40 Asymmetric hydrogenation of 4-chromanone usingRuCl(Tol-C4-teth-(S,S)-Msdpen)

In a 100-ml autoclave, 2.8 mg (0.00489 mmol, S/C=1000) ofRuCl(Tol-C4-teth-(S,S)-Msdpen) was placed, followed by purging withnitrogen. Subsequently, 0.72 g (5.0 mmol) of 4-chromanone and 4.4 ml ofmethanol were added thereto, and hydrogen was introduced to a pressureof 3.0 MPa, followed by stirring at 60° C. for 19 hours. The result ofGC analysis of the reaction liquid showed that (S)-4-chromanol wasobtained with a conversion of 100% and an optical purity of 97.6% ee.

Example 41 Production of RuBF₄ (Tol-C4-teth-(S,S)-Tsdpen)

In a 50-ml Schlenk tube, 0.26 g (0.4 mmol, 1 eq) ofRuCl(Tol-C4-teth-(S,S)-Tsdpen), 0.093 g (0.48 mmol, 1.2 eq) of AgBF₄, 8ml of dichloromethane, and 8 ml of methanol were mixed with each other,followed by stirring at room temperature for 1 hour. The reactionsolution was filtered through Celite, and the filtrate was evaporated todryness. Thus, 0.28 g of the target complex,RuBF₄(Tol-C4-teth-(S,S)-Tsdpen), was obtained (yield: 98%).

HRMS (ESI): calcd for C₃₃H₃₉ClN₂O₂RuS [M-BF₄]+ 629.1770. found 629.1768

INDUSTRIAL APPLICABILITY

The present invention provides a novel ruthenium complex. The rutheniumcomplex of the present invention has an extremely high catalyticactivity, and is hence useful as various hydrogenation catalysts.Furthermore, the ruthenium complex of the present invention is excellentin stereoselectivity, and hence useful as a catalyst for asymmetricreduction which achieves a high enantiomeric excess. Therefore, thepresent invention provides a ruthenium complex useful in the field ofthe industrial chemistry.

1. A ruthenium complex represented by the following general formula (1):

wherein R¹ represents an alkyl group having 1 to 10 carbon atoms; analkanesulfonyl group having 1 to 10 carbon atoms and optionallysubstituted with a halogen atom; an arenesulfonyl group optionallysubstituted with an alkyl group having 1 to 10 carbon atoms, ahalogenated alkyl group having 1 to 10 carbon atoms, or a halogen atom;an alkoxycarbonyl group having 2 to 11 carbon atoms in total; or abenzoyl group optionally substituted with an alkyl group having 1 to 10carbon atoms, R² and R³ each independently represent an alkyl grouphaving 1 to 10 carbon atoms; a phenyl group optionally substituted withan alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to10 carbon atoms, or a halogen atom; or a cycloalkyl group having 3 to 8carbon atoms, or R² and R³ may together form a ring, R¹⁰ to R¹⁴ eachindependently represent a hydrogen atom, an alkyl group having 1 to 10carbon atoms, an alkoxy group having 1 to 10 carbon atoms, or atrisubstituted alkylsilyl group, provided that the case where all of R¹⁰to R¹⁴ simultaneously represent hydrogen atoms is excluded, X representsa trifluoromethanesulfonyloxy group, a p-toluenesulfonyloxy group, amethanesulfonyloxy group, a benzenesulfonyloxy group, a hydrogen atom,or a halogen atom, j and k each represent 0 or 1, and j+k is 0 or
 2. 2.A ruthenium complex represented by the following general formula (1*):

wherein each * represents an asymmetric carbon atom, R¹ represents analkyl group having 1 to 10 carbon atoms; an alkanesulfonyl group having1 to 10 carbon atoms and optionally substituted with a halogen atom; anarenesulfonyl group optionally substituted with an alkyl group having 1to 10 carbon atoms, a halogenated alkyl group having 1 to 10 carbonatoms, or a halogen atom; an alkoxycarbonyl group having 2 to 11 carbonatoms in total; or a benzoyl group optionally substituted with an alkylgroup having 1 to 10 carbon atoms, R² and R³ each independentlyrepresent an alkyl group having 1 to 10 carbon atoms; a phenyl groupoptionally substituted with an alkyl group having 1 to 10 carbon atoms,an alkoxy group having 1 to 10 carbon atoms, or a halogen atom; or acycloalkyl group having 3 to 8 carbon atoms, or R² and R³ may togetherform a ring, R¹⁰ to R¹⁴ each independently represent a hydrogen atom, analkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10carbon atoms, or a trisubstituted alkylsilyl group, provided that thecase where all of R¹⁰ to R¹⁴ simultaneously represent hydrogen atoms isexcluded, X represents a trifluoromethanesulfonyloxy group, ap-toluenesulfonyloxy group, a methanesulfonyloxy group, abenzenesulfonyloxy group, a hydrogen atom, or a halogen atom, j and keach represent 0 or 1, and j+k is 0 or
 2. 3. A ruthenium complexrepresented by the following general formula (1′):

wherein each * represents an asymmetric carbon atom, R¹ represents analkyl group having 1 to 10 carbon atoms; an alkanesulfonyl group having1 to 10 carbon atoms and optionally substituted with a halogen atom; anarenesulfonyl group optionally substituted with an alkyl group having 1to 10 carbon atoms, a halogenated alkyl group having 1 to 10 carbonatoms, or a halogen atom; an alkoxycarbonyl group having 2 to 11 carbonatoms in total; or a benzoyl group optionally substituted with an alkylgroup having 1 to 10 carbon atoms, R² and R³ each independentlyrepresent an alkyl group having 1 to 10 carbon atoms; a phenyl groupoptionally substituted with an alkyl group having 1 to 10 carbon atoms,an alkoxy group having 1 to 10 carbon atoms, or a halogen atom; or acycloalkyl group having 3 to 8 carbon atoms, or R² and R³ may togetherform a ring, R¹⁰ to R¹⁴ each independently represent a hydrogen atom, analkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10carbon atoms, or a trisubstituted alkylsilyl group, provided that thecase where all of R¹⁰ to R¹⁴ simultaneously represent hydrogen atoms isexcluded, and Q^(⊖) represents a counter anion.
 4. (canceled)
 5. Aruthenium complex represented by the following general formula (2*), ora salt thereof:

wherein each * represents an asymmetric carbon atom, R¹ represents analkyl group having 1 to 10 carbon atoms; an alkanesulfonyl group having1 to 10 carbon atoms and optionally substituted with a halogen atom; anarenesulfonyl group optionally substituted with an alkyl group having 1to 10 carbon atoms, a halogenated alkyl group having 1 to 10 carbonatoms, or a halogen atom; an alkoxycarbonyl group having 2 to 11 carbonatoms in total; or a benzoyl group optionally substituted with an alkylgroup having 1 to 10 carbon atoms, R² and R^(3′) each independentlyrepresent an alkyl group having 1 to 10 carbon atoms; a phenyl groupoptionally substituted with an alkyl group having 1 to 10 carbon atoms,an alkoxy group having 1 to 10 carbon atoms, or a halogen atom; or acycloalkyl group having 3 to 8 carbon atoms, or R² and R³ may togetherform a ring, R¹⁰ to R¹⁴ each independently represent a hydrogen atom, analkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10carbon atoms, or a trisubstituted alkylsilyl group, provided that thecase where all of R¹⁰ to R¹⁴ simultaneously represent hydrogen atoms isexcluded, and X′ represents a halogen atom.
 6. A catalyst for asymmetricreduction, consisting of the ruthenium complex according to claim
 2. 7.A method for producing an optically active alcohol, comprising reducinga carbonyl group of a carbonyl compound in the presence of the rutheniumcomplex according to claim 2 and a hydrogen donor.
 8. A method forproducing an optically active amine, comprising reducing an imino groupof an imine compound in the presence of the ruthenium complex accordingto claim 2 and a hydrogen donor.
 9. The production method according toclaim 7, wherein the hydrogen donor is selected from formic acid, alkalimetal formates, and alcohols having a hydrogen atom on a carbon atom atan α-position of a carbon atom substituted with a hydroxyl group. 10.The production method according to claim 7, wherein the hydrogen donoris hydrogen gas.
 11. A catalyst for asymmetric reduction, consisting ofthe ruthenium complex according to claim
 3. 12. A catalyst forasymmetric reduction, consisting of the ruthenium complex according toclaim
 5. 13. A method for producing an optically active alcohol,comprising reducing a carbonyl group of a carbonyl compound in thepresence of the ruthenium complex according to claim 3 and a hydrogendonor.
 14. A method for producing an optically active alcohol,comprising reducing a carbonyl group of a carbonyl compound in thepresence of the ruthenium complex according to claim 5 and a hydrogendonor.
 15. A method for producing an optically active amine, comprisingreducing an imino group of an imine compound in the presence of theruthenium complex according to claim 3 and a hydrogen donor.
 16. Amethod for producing an optically active amine, comprising reducing animino group of an imine compound in the presence of the rutheniumcomplex according to claim 5 and a hydrogen donor.
 17. The productionmethod according to claim 8, wherein the hydrogen donor is selected fromformic acid, alkali metal formates, and alcohols having a hydrogen atomon a carbon atom at an α-position of a carbon atom substituted with ahydroxyl group.
 18. The production method according to claim 16, whereinthe hydrogen donor is selected from formic acid, alkali metal formates,and alcohols having a hydrogen atom on a carbon atom at an α-position ofa carbon atom substituted with a hydroxyl group.
 19. The productionmethod according to claim 8, wherein the hydrogen donor is hydrogen gas.20. The production method according to claim 13, wherein the hydrogendonor is hydrogen gas.
 21. The production method according to claim 14,wherein the hydrogen donor is hydrogen gas.